I have recently shown that gonadectomy and chronic sex hormone administration have substantial effects on cardiac contractile function and myosin enzymatic activity. I will attempt to confirm these effects were due to sex hormone deficiency per se by determining whether gonadectomy alters other cardioregulatory hormones, namely, insulin, thyroid hormone, growth hormone and the catecholamines. Since endogenous sex hormones are increased in pregnancy, intrinsic cardiac function and myosin biochemistry will be studied during pregnancy. I have observed slower cardiac relaxation in hearts from gonadectomized animals. In this proposal I will determine whether Ca2+ uptake is depressed in sarcoplasmic reticulum from these hearts and whether particular sex hormones modulate this site of intercellular Ca2+ regulation. Sex differences and the acute and chronic modulating influence of sex steroids on the cardiac chronotropic and inotropic response to catecholamines will be determined in perfused hearts. A biochemical basis for altered responsiveness will be sought in studies of alpha and beta receptor density and affinity. Differences in the incidence of heart disease in male and female humans are well known, but most research has focused on sex differences in coronary atherogenesis, lipoprotein metabolism and thromboembolism. I will test the hypothesis that sex differences occur in the myocardial response to ischemia by studying hearts of virgin rats, an animal model which is resistant to coronary atherosclerosis. Experiments on contractile and metabolic responses will be conducted in vitro in globally ischemic hearts where coronary flow is precisely controlled. Experiments will also be conducted to quantitatively measure vulnerability to ventricular fibrillation before and after coronary occlusion. Mechanisms responsible for differences in ventricular fibrillation will be sought in studies of adrenergic modulation, cyclic AMP production, and basic electrophysiological properties of ventricular muscle. These studies will address whether particular sex hormones are either chronically or acutely beneficial or harmful in the ischemic responses.